A new efficient stereoselective method for the synthesis of (E)-5-aminoallyl-pyrimidine-5′-triphosphates using palladium-catalyzed heck reaction

Article abstract of DOI:10.1080/15257770.2014.978013

An efficient overall two-step strategy for the synthesis of, starting from commercially available pyrimidine-5′-triphosphate is described. The method involves regioselective iodination of pyrimidine-5′-triphosphate, followed by the palladium-catalyzed Heck coupling with allylamine. The catalytic reaction is highly stereoselective and compatible with many functional groups present in the reactants.

Full text of DOI:10.1080/15257770.2014.978013

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A New Efficient Stereoselective Method
for the Synthesis of (E)-5-Aminoallyl-
Pyrimidine-5′-Triphosphates Using
Palladium-Catalyzed Heck Reaction
Anilkumar R. Korea, Annamalai Senthilvelana, Muthian
Shanmugasundarama, David Sandovala & Andrew Pardoa
a Life Sciences Solutions Group, Thermo Fisher Scientific, Austin,
TX, USA
Published online: 24 Feb 2015.
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To cite this article: Anilkumar R. Kore, Annamalai Senthilvelan, Muthian Shanmugasundaram, David
Sandoval & Andrew Pardo (2015) A New Efficient Stereoselective Method for the Synthesis of (E)-5-
Aminoallyl-Pyrimidine-5′-Triphosphates Using Palladium-Catalyzed Heck Reaction, Nucleosides,
Nucleotides and Nucleic Acids, 34:3, 221-228, DOI: 10.1080/15257770.2014.978013
To link to this article: http://dx.doi.org/10.1080/15257770.2014.978013
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Nucleosides, Nucleotides and Nucleic Acids, 34:221–228, 2015
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2014.978013
A NEW EFFICIENT STEREOSELECTIVE METHOD FOR THE
SYNTHESIS OF (E)-5-AMINOALLYL-PYRIMIDINE-5ꢀ-TRIPHOSPHATES
USING PALLADIUM-CATALYZED HECK REACTION
Anilkumar R. Kore, Annamalai Senthilvelan, Muthian Shanmugasundaram,
David Sandoval, and Andrew Pardo
Life Sciences Solutions Group, Thermo Fisher Scientific, Austin, TX, USA
An efficient overall two-step strategy for the synthesis of (E)-5-aminoallyl-pyrimidine-5ꢁ-
2
triphoshate, starting from commercially available pyrimidine-5ꢁ-triphosphate is described. The
method involves regioselective iodination of pyrimidine-5ꢁ-triphosphate, followed by the palladium-
catalyzed Heck coupling with allylamine. The catalytic reaction is highly stereoselective and compat-
ible with many functional groups present in the reactants.
Keywords Palladium; Heck-coupling; stereoselective; DNA; non-radioactive probe;
aminoallyl nucleotides
INTRODUCTION
The nucleic acid chemistry of C-5-substituted pyrimidine nucleotides has
been the subject of immense interest in view of their valuable applications
in various fields such as structural biology, chemical biology, nanobiotech-
nology, and DNA sensing.[1,2] In particular, aminoallyl nucleotides serve as
a versatile molecular biology tool for the introduction of functional groups
into a nucleic acid target of interest by using in vitro enzymatic incorporation
method.[3] The amine-modified DNA has been produced by the incorpora-
tion of aminoallyl pyrimidine nucleotides into DNA that utilizes enzymatic in-
corporation methods such as reverse transcription, nick translation, random
primed labeling or polymerase chain reaction (PCR). The amine-modified
DNA can be coupled with any amine-reactive dye or hapten for labeling
nucleic acid.[4–7] The attractive feature of the overall two-step techniques for
labeling nucleic acid is the generation of high degree of uniform DNA. This
powerful non-radioactive technique has been utilized for various molecu-
lar biology applications such as gene expression, chromosome, and mRNA
Received 11 September 2014; accepted 13 October 2014.
Address correspondence to Anilkumar R. Kore, Life Sciences Solutions Group, Thermo Fisher
Scientific, 2130 Woodward Street, Austin, TX 78744-1832, USA. E-mail: anil.kore@thermofisher.com
221

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A. R. Kore et al.
fluorescence in situ hybridization (FISH) experiment, mutation detection
on arrays and microarrays, in situ real time-polymerase chain reaction, and
PCR.[8–11] The incorporation of 5-(3-aminoallyl)-pyrimidine-5ꢁ-triphosphate
into RNA by T7 RNA polymerase produces aminoallyl-RNA that can be con-
jugated to an amine-reactive biotin or fluorescent dye to produce the labeled
RNA.[1] The use of such non-radioactive labeling outweighs radioactive la-
beling in terms of safety, speed, reliability, better stability, higher labeling
efficiency, and consistency at reduced cost. Given the stringent molecular bi-
ology assays, the high quality and purity of aminoallyl pyrimidine nucleotides
are critical for the successful results.
The most widely used route to make aminoallyl pyrimidine nucleotide in-
volves mercuration of pyrimidine-5ꢁ-triphosphate and subsequent palladium-
catalyzed reaction with allyamine.[12,13] However, this strategy suffers from
severe drawbacks such as the use of toxic and hazardous mercuric acetate and
the requirement of a large excess of this reagent. In addition, the isolation of
aminoallyl pyrimidine triphosphate free from mercury is a tedious and cum-
bersome process. Alternatively, the overall three chemical steps synthesis of
5-aminoallyl-dUTP, starting from 5-iodo-2ꢁ-deoxyuridine has been reported
by Sakthilvel and Barbas III. The first step involves palladium-catalyzed Heck
coupling reaction of 5-iodo-2ꢁ-deoxyuridine with protected allylamine. Then,
triphosphorylation of protected aminoallyl 2ꢁ-dexoyuridine-5ꢁ-triphosphate
using “One pot, three step strategy” and subsequent deprotection of the
allylamine moiety to afford the desired 5-(3-aminoallyl)-2ꢁ-dexoyuridine-5ꢁ-
triphosphate.[14] However, the overall three-step synthesis involving protec-
tion and deprotection strategy increases the complexity of the synthesis that
results in poor yields. Given the ever-growing molecular biology applications
toward in vitro transcription and post-synthetic labeling, the development of
a novel and efficient method to make aminoallyl pyrimidine nucleotides free
from mercury would be highly pursued target in order to meet the applica-
tion of nucleic acid chemistry demand. The use of palladium-catalyzed Heck
coupling reaction provides a powerful tool for the construction of C-C bonds
in nucleic acid chemistry.[15] Although the exploration of halogenated nucle-
osides for the palladium-catalyzed Heck coupling has been well documented
in the literature,[16–18] the use of halogenated nucleotides is under explored.
As part of our continuous interest in the area of nucleic acid chemistry,[19–25]
we were prompted to explore the possibility of palladium-catalyzed Heck
coupling reaction of 5-iodo-pyrimidine-5ꢁ-triphosphates with allylamine for
the synthesis of 5-aminoallyl-pyrimidine-5ꢁ-triphosphates. In our preliminary
communications, we reported the first example of highly stereoselective
palladium-catalyzed Heck coupling of 5-iodo-uridine-5ꢁ- triphosphates with
allylamine, leading to the formation of (E)-5-aminoallyl-uridine-5ꢁ- triphos-
phates.[26] In this article, we report the full details for the synthesis of 5-
aminoally-uridine nucleotides and the extension of this synthetic strategy to
make 5-aminoallyl-cytidine nucleotides in moderate yields with high purities.

Synthesis of (E)-5-Aminoallyl-Pyrimidine-5ꢁ-Triphosphates
RESULTS AND DISCUSSION
223
The two-step reaction pathway leading to the desired product
5-(3-aminoallyl)-2ꢁ-deoxyuridine-5ꢁ-triphosphate, AA-dUTP 3a and 5-(3-
aminoallyl)-uridine-5ꢁ-triphosphate, AA-UTP 3b is depicted in Scheme 1.
The required starting materials 2a and 2b were obtained by the iodination of
2ꢁ-deoxyuridine-5ꢁ-triphosphate, dUTP 1a and uridine-5ꢁ-triphosphate, UTP
1b with N-iodosuccinimide in the presence of sodium azide using water as
a solvent that furnished the corresponding 5-iodo-dUTP 2a and 5-iodo-UTP
2b in 79% and 80% yields, respectively.[27] The iodination reaction is highly
regioselective with the iodo group adds exclusively to the C-5 carbon of the
uridine moiety.[28] The final palladium-catalyzed Heck coupling of 5-iodo-
dUTP 2a and 5-iodo-UTP 2b with allylamine using K2PdCl4 as a catalyst
afforded the corresponding AA-dUTP 3a and AA-UTP 3b in 74% and 71%
yields, respectively. In both cases, the catalytic reaction is highly stereoselec-
tive, affording E-isomer with greater than 99%. The trans stereochemistry
for the product is determined by the coupling pattern for olefin protons
in aminoallyl moiety with large coupling constant. For example, one of the
olefinic protons of 3b resonates at δ 6.57 as a doublet with J = 16 Hz. In
addition to the high stereoselectivity, the reaction affords high purity prod-
uct (>99%) after DEAE Sepharose column purification as evidenced by the
high performance liquid chromatography (HPLC) data.
SCHEME 1 Synthesis of aminoallyl-dUTP 3a and aminoallyl-UTP 3b.
The scope and generality of the present palladium-catalyzed Heck cou-
pling reaction is further extended into cytidine derivatives (Scheme 2). The
iodination reaction of dCTP 4a and CTP 4b with N-iodosuccinimide in the
presence of sodium azide using water as a solvent at 60◦C afforded the
corresponding 5-iodo-dCTP 5a and 5-iodo-CTP 5b in 76% and 74% yields,
respectively.[27] The final palladium-catalyzed Heck coupling of 5-iodo-dCTP
5a and 5-iodo-CTP 5b with allylamine using K2PdCl4 as a catalyst at 60◦C fur-
nished the corresponding AA-dCTP 6a and AA-CTP 6b in 49% and 45%

224
A. R. Kore et al.
yields, respectively. The same reaction when carried out at room tempera-
ture did not afford the corresponding aminoallyl product 6.
SCHEME 2 Synthesis of aminoallyl-dCTP 6a and aminoallyl-CTP 6b.
There are several interesting features that deserve comments from the
present palladium-catalyzed Heck coupling reaction. First, the present cat-
alytic reaction is highly stereoselective that forms exclusive (E)-5-aminoallyl-
pyrimidine-5ꢁ-triphoshate. It is to be mentioned that the rate of dNTP incor-
poration during nucleic acid synthesis depends on the high E/Z geometry
of aminoallyl nucleotides. In addition, high E/Z geometry plays an impor-
tant role on the properties of final nucleic acid.[1,6] Second, unlike litera-
ture method utilizes toxic and hazardous mercuric acetate,[12,13] the present
method completely eliminates the use of mercury. Third, the protection of
allylamine is required for the literature known palladium-catalyzed Heck
coupling involving 5-iodo nucleosides[16–18] whereas the present Heck cou-
pling reaction works very well with allylamine without the need for protection
and de-protection. Fourth, the present catalytic Heck reaction is compati-
ble with a wide variety of functional groups such as hydroxyl, phosphorous,
amide, and amine groups. Finally, the purification procedure is simple,
easy, and straightforward that furnishes a final pure aminoallyl pyrimidine
nucleotide with extremely high purity, >99% in all cases.
In summary, we have developed a palladium-catalyzed Heck cou-
pling reaction of 5-iodo-pyrimidine-5ꢁ-triphosphate with allylamine. This
method allows an efficient synthesis of (E)-5-(3-aminoallyl)-pyrimidine-5ꢁ-
triphosphates in moderate to good yields with high purities. The catalytic
reaction is highly stereoselective and tolerates a wide variety of functional
groups such as hydroxyl, amide, phosphorous, and amine present in the
substrates. The present strategy outweighs the literature method in terms of
green chemistry that replaces the hazardous and toxic mercuric compound.

Synthesis of (E)-5-Aminoallyl-Pyrimidine-5ꢁ-Triphosphates
225
EXPERIMENTAL
General
All of the commercial reagents and solvents were used as such with-
out further purification. Pyrimidine nucleotide was obtained from Thermo
Fisher Scientific (Austin, Texas). The experimental procedure for the syn-
thesis of 5-(3-aminoallyl)-2ꢁ-deoxyuridine-5ꢁ-triphosphate (3a) was reported
in our earlier communication.[26] 1H NMR spectra were recorded in D2O
on a Bruker 400 MHz and 31P NMR were recorded on a Bruker 162 MHz.
Chemical shifts are reported in ppm, and signals are described as s (singlet),
d (doublet), t (triplet), q (quartet), and m (multiplet). Electrospray ion-
ization mass was recorded on an Applied Biosystems/Sciex MDX API 150
model. HPLC was run on a Waters 2996 (Waters Corporation) using Hyper-
sil SAX column. FPLC (fast protein liquid chromatography) was performed
¨
on a AKTA purifier (GE Healthcare) using DEAE Sepharose column.
Synthesis of 5-(3-aminoallyl)-uridine-5ꢀ-triphosphate (3b)
To a stirred solution of 5-iodo-uridine-5ꢁ-triphosphate 2b (1.00 g,
1.10 mmol) in 0.1 M sodium acetate (50 mL) at room temperature, K2PdCl4
(0.25 g, 0.77 mmol) was added and the mixture was stirred for 5 minutes.
A pre-chilled cocktail containing allylamine (1.22 mL, 16.33 mmol) and
4 M acetic acid in 0.1 M sodium acetate (10 mL) was added to the reaction
mass and kept under stirring for 15 hours. The reaction mixture was filtered
through a 0.2 μM, 1000 mL Nalgene filtration unit. The collected aqueous
solution was adjusted to pH 6.5 and loaded on a DEAE Sepharose column.
The desired product was eluted using a linear gradient of 0–1 M triethylam-
monium bicarbonate (TEAB) and the fractions containing the product were
pooled, evaporated, and co-evaporated with water (3 × 100 mL). The TEA
salt of AA-UTP thus obtained was subjected to ion-exchange with sodium
perchlorate (5.0 g) in acetone (200.0 mL) to afford the sodium salt of AA-
1
UTP 3b (0.47 g, 71%). H NMR (D2O, 400 MHz) δ 8.15 (s, 1H), 6.57 (d, J
= 16.0 Hz, 1H), 6.48 (dt, J = 16.0, 6.4 Hz, 1H), 6.01 (d, J = 4.4 Hz, 1H),
4.46–4.27 (m, 5H), 3.74 (d, J = 6.0 Hz, 2H); 31P NMR (D2O, 162 MHz) δ
−8.85 (d, J = 17.8 Hz, 1P), −10.14 (d, J = 18.1 Hz, 1P), −21.42 (t, J =
19.6 Hz, 1P); MS (m/z): 538 [M–H]+.
Synthesis of 5-(3-aminoallyl)-2ꢀ-deoxycytidine-5ꢀ-
triphosphate (6a)
To a stirred solution of 5-iodo-2ꢁ-deoxycytidine-5ꢁ-triphosphate 5a (0.50 g,
0.56 mmol) in 0.1 M sodium acetate (25 mL) at room temperature, K2PdCl4
(0.13 g, 0.40 mmol) was added and the mixture was stirred for 5 minutes.
A pre-chilled cocktail containing allylamine (0.63 mL, 8.43 mmol) and 4 M

226
A. R. Kore et al.
acetic acid in 0.1 M sodium acetate (5 mL) was added to the reaction mass
and kept under stirring at 60◦C for 15 hours. The reaction mixture was
filtered through a 0.2 μM, 1000 mL Nalgene filtration unit. The collected
aqueous solution was adjusted to pH 6.5 and loaded on a DEAE Sepharose
column. The desired product was eluted using a linear gradient of 0–1 M
TEAB and the fractions containing the product were pooled, evaporated,
and co-evaporated with water (3 × 50 mL). The TEA salt of AA-dCTP thus
obtained was subjected to ion-exchange with sodium perchlorate (2.5 g) in
acetone (100.0 mL) to afford the sodium salt of AA-dCTP 6a (0.16 g, 49%).
1H NMR (D2O, 400 MHz) δ 8.26 (s, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.47
(dt, J = 16.0, 6.4 Hz, 1H), 6.30 (t, J = 6.4 Hz, 1H), 4.61 (m, 1H), 4.30–4.15
(m, 3H), 3.73 (d, J = 6.4 Hz, 2H), 2.39 (m, 2H); 31P NMR (D2O, 162 MHz)
δ −8.63 (d, J = 19.4 Hz, 1P), −10.57 (d, J = 20.1 Hz, 1P), −21.97 (t, J =
19.8 Hz, 1P); MS (m/z): 521 [M–H]+.
Synthesis of 5-(3-aminoallyl)-cytidine-5ꢀ-triphosphate (6b)
To a stirred solution of 5-iodo-cytidine-5ꢁ-triphosphate 5b (0.50 g,
0.55 mmol) in 0.1 M sodium acetate (50 mL) at room temperature, K2PdCl4
(0.13 g, 0.40 mmol) was added and the mixture was stirred for 5 minutes.
A pre-chilled cocktail containing allylamine (0.62 mL, 8.30 mmol) and 4 M
acetic acid in 0.1 M sodium acetate (5 mL) was added to the reaction mass
and kept under stirring at 60◦C for 15 hours. The reaction mixture was
filtered through a 0.2 μM, 1000 mL Nalgene filtration unit. The collected
aqueous solution was adjusted to pH 6.5 and loaded on a DEAE Sepharose
column. The desired product was eluted using a linear gradient of 0–1 M
TEAB and the fractions containing the product were pooled, evaporated,
and co-evaporated with water (3 × 50 mL). The TEA salt of AA-CTP thus
obtained was subjected to ion-exchange with sodium perchlorate (2.5 g) in
acetone (100.0 mL) to afford the sodium salt of AA-CTP 6b (0.15 g, 45%).
1H NMR (D2O, 400 MHz) δ 8.25 (s, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.49 (dt,
J = 16.0, 6.8 Hz, 1H), 5.95 (d, J = 4.8 Hz, 1H), 4.46–4.10 (m, 5H), 3.72 (d,
J = 6.4 Hz, 2H); 31P NMR (D2O, 162 MHz) δ −8.62 (d, J = 19.4 Hz, 1P),
−10.74 (d, J = 20.1 Hz, 1P), −21.91 (t, J = 19.8 Hz, 1P); MS (m/z): 537
[M–H]+.
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